ramipril and Hyperglycemia

Despite extensive documentation of their insulin-sensitizing and antihyperglycemic effects, the importance and place of the thiazolidinediones in diabetes management remain unclear. Three new controlled clinical trials of thiazolidinediones offer new information on the clinical utility of these agents.. During the past year, three new trials of thiazolidinediones were reported. In Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication, rosiglitazone reduced progression to diabetes in prediabetic patients by 60%. A Diabetes Outcome Progression Trial found rosiglitazone to have greater antihyperglycemic durability than metformin and glyburide in patients with recently diagnosed type 2 diabetes. Finally, in the Carotid Intima-media Thickness in Atherosclerosis using Pioglitazone, treatment with pioglitazone in patients with type 2 diabetes slowed progression of carotid wall thickness compared with the sulfonylurea glimepiride.. These trials support the contention that thiazolidinediones have superior efficacy in improving and stabilizing glycemic control than older antihyperglycemic agents, especially early in the course of type 2 diabetes. Findings from the Carotid Intima-media Thickness in Atherosclerosis using Pioglitazone add to the evidence that these agents have clinically meaningful vasculoprotective effects. Although generally well tolerated, they promote weight gain, limiting their acceptability to some extent, and occasionally lead to a diagnosis of heart failure, mostly in susceptible individuals.

Topics: Adult; Aged; Carotid Arteries; Clinical Trials as Topic; Diabetes Mellitus; Disease Progression; Female; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Ramipril; Rosiglitazone; Thiazolidinediones

Risk of Type 2 diabetes varies by ethnicity, but whether ethnicity remains important among those who have impaired glucose tolerance or impaired fasting glucose is uncertain. Whether the effect of thiazolidinedione treatment on diabetes prevention in persons with non-diabetic dysglycaemia varies by ethnicity is also not known. We addressed these questions using data collected in the DREAM trial.. A 2-by-2 factorial double-blind randomized controlled trial to compare the effects of rosiglitazone and ramipril on the primary outcome of diabetes or death in persons meeting criteria for impaired glucose tolerance or impaired fasting glucose. The effect of these interventions by ethnicity was estimated using Cox regression analysis.. Of 5269 adults, 2365 were randomly assigned to rosiglitzone and 2634 to placebo. South Asians showed a higher hazard for the primary outcome compared with Europeans (hazard ratio, 95% confidence interval 2.21, 1.41-3.47) adjusted for age, gender, BMI, waist-hip ratio and geographic region. A lesser increase in risk was seen in Black people (1.37, 1.04-1.81). A significant reduction in risk of the primary outcome with rosiglitazone treatment assignment was seen in all ethnic groups, but the treatment effect significantly differed by ethnicity (P=0.0242), with South Asians experiencing a smaller, and Latinos a larger preventive effect.. Ethnicity is an important risk factor for Type 2 diabetes in dysglycaemic persons. All ethnic groups experienced a large significant reduction in diabetes risk because of rosiglitazone. The magnitude of this reduction differed by ethnicity. Given the post hoc nature of this analysis, further confirmation of these findings is needed.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucose Intolerance; Humans; Hyperglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Ramipril; Risk Assessment; Rosiglitazone; Thiazolidinediones

The aim of this study was to evaluate effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril and the thiazolidinedione (TZD) rosiglitazone on carotid intima-media thickness (CIMT) in people with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG).. People with IGT and/or IFG are at increased long-term risk for cardiovascular disease. Effects of ACE inhibitors and of TZDs on vascular disease in this population are unknown.. One thousand four hundred twenty-five people with IGT and/or IFG but without cardiovascular disease or diabetes were randomized to ramipril 15 mg/day or its placebo and to rosiglitazone 8 mg/day or its placebo with a 2 x 2 factorial design. The primary study outcome was the annualized change of the aggregate maximum CIMT, computed as the average of the maximum CIMTs across 12 carotid arterial segments. The secondary study outcome was the annualized change of the mean far wall left and right common CIMT. Median follow-up was 3 years and carotid ultrasound examinations were obtained at baseline and yearly thereafter.. There were no differences in the primary and secondary outcomes between the ramipril and placebo groups. Compared with placebo, rosiglitazone reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0027 +/- 0.0015 mm/year; p = 0.08) and significantly reduced the secondary CIMT outcome (difference = 0.0043 +/- 0.0017 mm/year; p = 0.01).. In people with IGT and/or IFG without cardiovascular disease and diabetes, treatment with ramipril had a neutral effect on CIMT, whereas rosiglitazone modestly reduced CIMT progression. (The Study of Atherosclerosis With Ramipril and Rosiglitazone; NCT00140647).

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Carotid Arteries; Carotid Artery Diseases; Fasting; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Ramipril; Rosiglitazone; Single-Blind Method; Thiazolidinediones; Tunica Intima; Ultrasonography

Patients with diabetes mellitus (DM) are at high risk of developing congestive heart failure (CHF). However, the relationships between glucose levels and CHF in people with or without a history of DM have not been well characterized.. We evaluated the associations between fasting plasma glucose and risk of hospitalization for CHF during follow-up in patients at high cardiovascular risk and without CHF enrolled in a large-scale clinical trials program. Baseline fasting plasma glucose levels were assessed in 31,546 high-risk subjects with > or = 1 coronary, peripheral, or cerebrovascular disease or DM with end-organ damage who are participating in 2 ongoing parallel trials evaluating the effects of telmisartan, ramipril, or their combination (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; n=25,620) and the effects of telmisartan against placebo in angiotensin-converting enzyme-intolerant patients (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease [TRANSCEND]; n=5926). Interim analyses blinded for randomized treatment were performed to compare baseline fasting plasma glucose with the adjusted CHF event rate at a mean follow-up of 886 days. Multivariable Cox regression models were performed, and associations were reported as hazard ratios and 95% confidence intervals. Among all subjects (mean age, 67 years; 69% men), of whom 11,708 (37%) had known DM and 1006 (3.2%) had newly diagnosed DM at baseline, 668 patients were hospitalized for CHF during follow-up. After adjustment for age and sex, a 1-mmol/L-higher fasting plasma glucose was associated with a 1.10-fold-increased risk of CHF hospitalization (95% confidence interval, 1.08 to 1.12; P<0.0001). The association persisted after adjustment for age, sex, smoking, previous myocardial infarction, hypertension, waist-to-hip ratio, creatinine, DM, and use of aspirin, beta-blockers, or statins (hazard ratio, 1.05; 95% confidence interval, 1.02 to 1.08; P<0.001).. Fasting plasma glucose is an independent predictor of hospitalization for CHF in high-risk subjects. These data provide theoretical support for potential direct beneficial effects of glucose lowering in reducing the risk of CHF and suggests the need for specific studies targeted at this issue.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Glucose; Diabetes Complications; Drug Therapy, Combination; Fasting; Female; Heart Failure; Hospitalization; Humans; Hyperglycemia; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Ramipril; Risk Factors; Telmisartan

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hyperglycemia; Hypoglycemic Agents; Ramipril; Rosiglitazone; Thiazolidinediones

DREAM ("Diabetes Reduction Assessment with ramipril and rosiglitazone Medication") is a double-blind randomised placebo-controlled clinical trial with a 2-by-2 factorial design aiming to study the effects of an ACE inhibitor (ramipril 15 mg/day) and/or a thiazolidinedione (rosiglitazone 8 mg/day) on the development of diabetes or death (primary outcome) and on the regression to normoglycaemia (secondary outcome) in 5269 adults aged 30 years or more with impaired fasting glucose and/or impaired glucose tolerance, and no previous cardiovascular disease. There was no statistical evidence of an interaction between the ramipril and the rosiglitazone arms. After a mean follow up of 3 years, the use of ramipril does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycaemia. In contrast, the treatment with rosiglitazone reduces by almost 60% the incidence of type 2 diabetes and increases the likelihood (+70%) of regression to normoglycaemia. Whether it is a true prevention effect or simply a treatment effect remains to be determined when participants will be retested after a washout period. Cardiovascular event rates were rather low and much the same in all treatment groups, except a higher rate of heart failure in the rosiglitazone group. These results suggest that the routine inhibition of the renin-angiotensin system for the express purpose of preventing diabetes is not indicated in individuals not at high risk for cardiovascular disease and appear to confirm the promises of the glitazone use in the very early stage of the natural history of type 2 diabetes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Ramipril; Rosiglitazone; Thiazolidinediones

In patients with insulin-dependent diabetes mellitus (IDDM) angiotensin-converting enzyme inhibitors (ACEI) have been demonstrated to have beneficial effects in the secondary prevention of microvascular complications. There are only few data available regarding the effect of ACEI on microcirculation in patients with IDDM without any microvascular complications. In addition, there is little knowledge about ACEI action during acute hyperglycemia. In a pilot study nine patients with IDDM without any clinical signs of diabetic complications (5 females, 4 males, aged 33.3 +/- 1.0 years, duration of diabetes 11.4 +/- 3.0 years, HbA1 7.2 +/- 0.2% [normal range 4.8-7.4%], BMI 21.4 +/- 0.5 [kg/m2]) received 1.25 mg of the ACEI ramipril (Delix, Hoechst Marion Roussel, Frankfurt) over 4 weeks. Nine healthy volunteers (4 females, 5 males, age 27.4 +/- 1.1 years, HbA1 5.9 +/- 0.2% (p < 0.01 vs patients), BMI 22.2 +/- 0.9 [kg/m2]) served as controls. Using nailfold capillaroscopy we determined capillary blood cell velocity (CapiFlow, Lawrenz Electronics, Sulzbach, Germany) before and during post-occlusive hyperemia (200 mmHg for 3 minutes) as a provocative test. Before and after treatment patients were studied during hyperglycemia (blood glucose 250-350 mg/dl). Treatment with low-dose ramipril resulted in a significant decrease in the time to peak capillary blood cell velocity during post-occlusive hyperemia (17.8 +/- 7.7 vs 57.4 +/- 12.8 s, p < 0.01) in hyperglycemic patients. This effect was absent in healthy volunteers. Hemodynamic and metabolic parameters remained unchanged throughout the study in both groups. These data demonstrate that low-dose therapy with the ACEI ramipril is able to improve microcirculation in hyperglycemic patients with type 1 diabetes mellitus also before microvascular complications are evident. Prospective studies are necessary to evaluate whether this effect might be clinically relevant in the primary prevention of diabetic microangiopathy.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Blood Pressure; Blood Viscosity; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dose-Response Relationship, Drug; Female; Fibrinogen; Glycated Hemoglobin; Heart Rate; Hematocrit; Humans; Hyperglycemia; Lipids; Male; Microcirculation; Ramipril; Triglycerides

An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril.. Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis.. Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy.. These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.

Topics: Animals; Antihypertensive Agents; Apoptosis; Cardiomegaly; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Endomyocardial Fibrosis; Female; Hyperglycemia; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Oxidative Stress; Proto-Oncogene Proteins c-akt; Ramipril; Superoxides; Ubiquinone; Ultrasonography; Ventricular Remodeling; Vitamins

Diabetes mellitus (DM) is a worldwide epidemic. Its prevalence is rapidly increasing in both developing and developed countries. Coronary heart disease (CHD) is highly prevalent and is the major cause of morbidity and mortality in patients with diabetes. Individuals with prediabetes states, with or without known CHD, should undergo lifestyle modifications aimed at preventing DM. In patients with CHD and DM, routine use of aspirin and an angiotensin-converting enzyme inhibitor, along with strict glycemic, blood pressure, and lipid control, is strongly recommended. Intense insulin therapy may be needed for glycemic control, and high-dose statin therapy may be needed for lipid control. For blood pressure control, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are considered first-line therapy. Noncompliance with medications and/or lifestyle measures and underprescription of evidence-based therapies remain important unsolved problems.

Topics: Antihypertensive Agents; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Life Style; Myocardial Infarction; Obesity; Pioglitazone; Piperidines; Platelet Aggregation Inhibitors; Prediabetic State; Pyrazoles; Ramipril; Rimonabant; Risk Assessment; Thiazolidinediones; Triglycerides; Weight Loss

ACE inhibition protects kidney function, but ACE insertion/deletion (I/D) polymorphism affects renal prognosis in type 1 diabetic patients. ACE genotype may influence the renal benefits of ACE inhibition. We studied the impact of ACE I/D polymorphism on the renal hemodynamic changes induced by ACE inhibition in type 1 diabetes. We studied renal hemodynamics (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], filtration fraction [GFR/ERPF], mean arterial pressure [MAP], and total renal resistances [MAP/ERPF]) repeatedly during normoglycemia and then hyperglycemia in 12 normotensive, normoalbuminuric type 1 diabetes and the II genotype (associated with nephroprotection) versus 22 age- and sex-matched subjects with the ACE D allele after three randomly allocated 2- to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.

Topics: Adult; Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Female; Gene Deletion; Genotype; Glomerular Filtration Rate; Hemodynamics; Humans; Hyperglycemia; Kidney; Male; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Ramipril; Renin

Angiotensin-converting enzyme inhibitors and alpha1-adrenoceptor antagonists improve glucose disposal in diabetes mellitus. We compared the effect of the antihypertensive hybrid drug urapidil [alpha1-adrenoceptor antagonist serotonin 1A (5-hydroxytryptamine 1A, 5-HT1A) receptor agonist] on hyperglycemia in streptozotocin diabetic rats with the angiotensin-converting enzyme inhibitor ramipril. 5-HT1A receptor agonists induce hyperglycemia. This could be an important disadvantage during treatment of diabetes mellitus with urapidil. Diabetes was induced by streptozotocin (70 mg/kg i.p.). Treatment for 7 days (ramipril 10 mg/kg p.o.; urapidil 20 mg/kg p.o.) significantly decreased mean blood glucose values (urapidil: 15.7+/-0.9 mmol/l, P=0.007; ramipril: 15.0+/-0.8 mmol/l, P=0.038 vs. diabetic control group: 18.7+/-1.0 mmol/l). Both drugs reduced significantly blood pressure, urinary glucose, water consumption, and food requirement. Serotonin concentration in the brain (medulla oblongata, pituitary) was not affected. A normalization comparable with healthy control rats was observed only in a diabetic control group with insulin therapy. In conclusion, our results demonstrate that the antihypertensive drug urapidil has no detrimental effect on hyperglycemia compared with the angiotensin-converting enzyme inhibitor ramipril in experimental diabetes mellitus despite its 5-HT1A receptor agonistic properties.

Topics: Adrenergic alpha-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Drinking; Eating; Glycosuria; Hyperglycemia; Insulin; Male; Medulla Oblongata; Piperazines; Pituitary Gland; Ramipril; Rats; Rats, Inbred WKY; Serotonin; Serotonin Receptor Agonists

The kallikrein-kinin system (KKS) has been postulated to play a role in modulation of hemodynamic function in diabetes and to contribute to the hemodynamic effects of angiotensin-converting enzyme inhibition (CEI). To further explore the KKS and its interactions with the renin-angiotensin system (RAS), studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic rats. In protocol 1, control and diabetic rats were studied before and after administration of one of two dissimilar B2 kinin receptor antagonists (BK2As), or vehicle. At a low dose (0.5 microg x kg-1 x min-1), the first generation antagonist D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin significantly reduced the glomerular filtration rate (GFR) and renal plasma flow rate in diabetic rats, despite variable effectiveness in blocking the hypotensive response to injected bradykinin. However, a similar hemodynamic effect occurred in nondiabetic rats, suggesting that the observed effect was not specific to diabetes. Higher doses (20 microg bolus, then 1 microg x kg-1 x min-1 infusion) did not affect hemodynamics in either group, perhaps because of partial agonist effect. The second BK2A tested was the newer compound, icatibant (Hoe 140; D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). Hoe 140 consistently blocked the vasodepressor action of injected bradykinin, but had no effect on systemic or renal hemodynamics in either control or diabetic rats. In protocol 2, control and diabetic rats were pretreated with the CEI ramipril for 1-2 weeks, after which renal function was studied before and after Hoe 140 (0.1 mg s.c. and i.v.) or vehicle. CEI lowered blood pressure in both groups. Hoe 140 did not affect renal function in control rats, but in diabetic rats pretreated with ramipril, it induced a modest but significant decline in GFR. Ramipril induced the predicted changes in the systemic and intrarenal RAS, while acute BK2A had no consistent effect on RAS parameters. These studies suggest that the endogenous KKS has only a minor role in modulation of renal hemodynamics in the euvolemic diabetic rat, in the absence of KKS stimulation by CEI. However, angiotensin-converting enzyme is also kininase II, which serves to increase endogenous kinin activity. The increased kinin activity resulting from CEI treatment may participate, to a modest degree, in hemodynamic regulation of the diabetic kidney.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Bradykinin; Bradykinin Receptor Antagonists; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Hemodynamics; Hyperglycemia; Kallikreins; Kidney; Kinins; Male; Organ Size; Ramipril; Rats; Rats, Wistar; Receptor, Bradykinin B2; Renal Circulation; Renin-Angiotensin System